This is the revised version of the first competing renewal of a Program Project (PP) focused on investigating the role that age-related changes in autophagy play in the functional alterations and inefficient response to immunological challenges and to stress of old organisms. Autophagy is a basic catabolic pathway essential for the maintenance of cellular homeostasis, regulation of the cellular energetic balance and an integral part of the response to stress. The components of the PP are four Projects involving 6 faculty members from 5 academic departments and three Cores that provide support to the research activities of the four projects. The projects share ideas, techniques and experimental models. Completion of aims requires participation of members from several of the projects. The PPG activities are reviewed periodically by a 6-member Scientific Advisory Committee. The long-term goal of the PP remains testing the overall hypothesis that impairment in autophagy mediates the functional deterioration and the inability to orchestrate an efficient response to stressors and to immunological challenges in old organisms. Building on the novel findings of the previous period, we propose now the following specific aims: 1) to characterize the involvement of different autophagic pathways, including endosomal-microautophagy (eMI), in the cellular response to stress with the focus now on proteotoxicity, lipotoxicity and genotoxicity in liver, brain (P1), adipose tissue (P4) and immune system (P2, P3); 2) to determine the impact of age-related changes in the different autophagic pathways on the immune response (P2, P3), adipose tissue homeostasis and remodeling (P4) and in the organismal resistance to stress (P1); 3) to analyze the effect of different interventions that modulate the activity of different autophagic pathways on the metabolic changes associated with aging (P1, P4) and on the failure of two essential immune functions, antigen processing and presentation (P2) and T cell activation (P3). These studies will require the synergistic cooperation of groups with expertise in autophagy, dendritic cell function, T cell biology, lipid metabolism, medicinal chemistry and oxidative cellular injury. Relevance: This PP explores the novel concepts that: 1. defective autophagic function is behind the higher vulnerability to stressors of old organisms and that 2. interventions aimed at restoring or enhancing autophagy could be implemented as anti-aging strategies to prolong health-span. Our studies may ultimately lead to fundamental insights in understanding, treating or preventing the metabolic alterations and declined cognitive and immune function of elders through manipulations of the autophagic system.